Subcutaneous administration of drugs and hydration in acute palliative care units: Physician attitudes and beliefs in the United States and Canada.

OBJECTIVES: The objective of this study was to compare the attitudes and beliefs of PCU physicians leaders in the United States versus Canada regarding the subcutaneous method in the administration of medications and hydration in order to gain a better understanding as to why variations in practice exist. METHODS: This survey trial took place from November 2022 to May 2023. The MD Anderson Cancer Center institutional review board in Houston, Texas, approved this study. The participants were the physician leaders of the acute palliative care units (PCUs) in the United States and Canada. The survey comprised questions formulated by the study investigators regarding the perceived comfort, efficiency, and preference of using the subcutaneous versus the intravenous method. The consent form and survey links were emailed to the participants. RESULTS: Sixteen PCUs were identified in the United States and 15 PCUs in Canada. Nine US and 8 Canadian physicians completed the survey. Physicians in Canada were more likely to use the subcutaneous route for administering opioids, antiemetics, neuroleptics, and hydration. They preferred subcutaneous over intravenous or intramuscular routes (p = 0.017). Canadian physicians felt their nursing staff was more comfortable with subcutaneous administration (p = 0.022) and that it was easier to administer (p = 0.02). US physicians felt the intravenous route was more efficient (p = 0.013). SIGNIFICANCE OF RESULTS: The study results suggest that exposure to the subcutaneous route influences a physician's perception. Further research is needed to explore ways to incorporate its use to a greater degree in the US healthcare system.

What is the impact of clinically assisted hydration in the last days of life? A systematic literature review and narrative synthesis.

BACKGROUND: Clinically assisted hydration (CAH) can be provided in the last days of life as drinking declines. The impact of this practice on quality of life or survival in the last days of life is unclear. Practice varies worldwide concerning this emotive issue. METHOD: Systematic literature review and narrative synthesis of studies evaluating the impact of, or attitudes toward, CAH in the last days of life. Databases were searched up to December 2019. Studies were included if the majority of participants were in the last 7 days of life, and were evaluated using Gough's 'Weight of Evidence' framework. Review protocol registered with PROSPERO, registration number CRD42019125837. RESULTS: Fifteen studies were included in the synthesis. None were judged to be both of high quality and relevance. No evidence was found that the provision of CAH has an impact on symptoms or survival. Patient and family carer attitudes toward assisted hydration were diverse. CONCLUSION: There is currently insufficient evidence to draw firm conclusions on the impact of CAH in the last days of life. Future research needs to focus on patients specifically in the last days of life, include those with non-malignant diagnoses, and evaluate best ways to communicate effectively about this complex topic with patients and their families.

Emergency nurses' experiences of the implementation of early goal directed fluid resuscitation therapy in the management of sepsis: a qualitative study.

BACKGROUND: Severe sepsis can lead to organ failure and death if immediate treatment, such as intravenous fluids and antibiotics, are not commenced within the first hour. Time - critical initiation of intravenous fluids which in other words is early goal directed fluid resuscitation has not always been given its clinical priority. This qualitative study aimed at exploring the experiences of emergency nurses initiating early goal directed fluid resuscitation in patients with sepsis. METHODS: Using an exploratory approach, face - to - face semi - structured interviews were conducted with ten registered nurses working in emergency departments across New South Wales, Australia. Thematic analysis was used for data analysis. FINDINGS: Participants described various factors that inhibited the timely initiation of early goal directed fluid resuscitation, some clinical practice challenges, and strategies to improve nursing practice. Most participants, particularly those practicing as Clinical Initiatives Nurses suggested the incorporation of nurse initiated early goal directed fluid resuscitation for patients with sepsis as part of their scope of practice. CONCLUSION: Our findings identified several barriers that inhibit effective nurse - initiated early goal directed fluid resuscitation. It is anticipated that these findings will provide validation for the re-evaluation of the existing protocols and practice guidelines to increase the scope of practice of emergency nurses initiating early goal directed fluid resuscitation.

Inputs to Thirst and Drinking during Water Restriction and Rehydration.

Current models of afferent inputs to the brain, which influence body water volume and concentration via thirst and drinking behavior, have not adequately described the interactions of subconscious homeostatic regulatory responses with conscious perceptions. The purpose of this investigation was to observe the interactions of hydration change indices (i.e., plasma osmolality, body mass loss) with perceptual ratings (i.e., thirst, mouth dryness, stomach emptiness) in 18 free-living, healthy adult men (age, 23 ± 3 y; body mass, 80.09 ± 9.69 kg) who participated in a 24-h water restriction period (Days 1-2), a monitored 30-min oral rehydration session (REHY, Day 2), and a 24-h ad libitum rehydration period (Days 2-3) while conducting usual daily activities. Laboratory and field measurements spanned three mornings and included subjective perceptions (visual analog scale ratings, VAS), water intake, dietary intake, and hydration biomarkers associated with dehydration and rehydration. Results indicated that total water intake was 0.31 L/24 h on Day 1 versus 2.60 L/24 h on Day 2 (of which 1.46 L/30 min was consumed during REHY). The increase of plasma osmolality on Day 1 (297 ± 4 to 299 ± 5 mOsm/kg) concurrent with a body mass loss of 1.67 kg (2.12%) paralleled increasing VAS ratings of thirst, desire for water, and mouth dryness but not stomach emptiness. Interestingly, plasma osmolality dissociated from all perceptual ratings on Day 3, suggesting that morning thirst was predominantly non-osmotic (i.e., perceptual). These findings clarified the complex, dynamic interactions of subconscious regulatory responses with conscious perceptions during dehydration, rehydration, and reestablished euhydration.

Theory-Based Interventions to Promote Fluid Intake Adherence Among Dialysis Patients: A Systematic Review.

BACKGROUND AND PURPOSE: Dialysis involves a complex regimen including diet, fluid, medication, and treatment. Therapeutic regimen adherence determines the therapeutic success, quality of life, and survival of patients on dialysis. Complying with fluid management is the most difficult among the therapeutic regimen. Several theory-based interventions have been designed to promote fluid intake compliance in patients receiving dialysis. This review has two aims. One is to explore the effectiveness of theory-based interventions. The other is to examine the extent of the combination of theory and interventions in improving adherence to fluid intake among dialysis patients. METHODS: A literature review was performed using PubMed, PsycINFO, Embase, Web of Science, and the Cochrane Library to acquire associated studies. Data were extracted independently by two researchers. The degree of theory application was accessed using a theory coding scheme (TCS). RESULTS: Eight studies were identified as eligible for inclusion, and five theories were cited as basis (health belief model, social cognitive theory, self-regulation model, transtheoretical model). According to the TCS, adherence outcomes and the extent of theory use were not optimal. IMPLICATIONS FOR PRACTICE: Combining theory with patient health education might be beneficial in improving fluid intake adherence of dialysis patients. The framework and TCS could be considered to guide theory utilization and promote nursing education in improving the quality of renal nursing care.

Effects of Dehydration and Rehydration on Cognitive Performance and Mood among Male College Students in Cangzhou, China: A Self-Controlled Trial.

Water accounts for 75% of brain mass. Associations may exist between hydration and cognitive performance. The objective of this study was to investigate the effects of dehydration and rehydration on cognitive performance and mood. In this self-control trial, 12 men were recruited from a medical college in Cangzhou, China. After 12 h of overnight fasting, the participants took baseline tests at 8:00 AM on day 2. First morning urine and blood osmolality were analyzed to determine hydration state. Height, weight, and blood pressure were measured following standardized procedures. A visual analog scale for the subjective sensation of thirst was applied, and a profile of mood states questionnaire was applied. Tests were conducted for cognitive performance, including a test of digit span forward and backward, digit-symbol substitutions, dose-work, and stroop effects. Participants were required not to drink water for 36 h but were given three meals on day 3. On day 4, the same indexes were tested as a baseline test. At 8:30 AM, participants drank 1500 mL of purified water over 15 min. After a 1 h interval, the same measurements were performed. Compared with baseline test results, during the dehydration test, participants had lower scores of vigor (11.9 vs. 8.8, %, p = 0.007) and esteem-related affect (8.2 vs. 5.7, %, p = 0.006), lower total scores of digit span (14.3 vs. 13.3, %, p = 0.004), and higher error rates for dose-work (0.01 vs. 0.16, %, p = 0.005). Compared with the dehydration test scores, rehydration test scores showed that fatigue (4.3 vs. 2.1, %, p = 0.005) and total mood disturbance (TMD) (99.0 vs. 90.2, %, p = 0.008) improved, and scores of forward, backward, and total digit span increased (7.7 vs. 8.6, p = 0.014; 5.7 vs. 1.2, p = 0.019; 13.3 vs. 15.4, p = 0.001). Increases were also noted in correct number of digit symbol substitutions, reading speed, and mental work ability (70.8 vs. 75.4, p < 0.001; 339.3 vs. 486.4, n/min, p < 0.001; 356.1 vs. 450.2, p < 0.001), and reaction time decreased (30.2 vs. 28.7, s, p = 0.002). As a conclusion, dehydration had negative effects on vigor, esteem-related affect, short-term memory, and attention. Rehydration after water supplementation alleviated fatigue and improved TMD, short-term memory, attention, and reaction.

Patients' perceptions of their experience, control and knowledge of fluid management when receiving haemodialysis.

BACKGROUND: Person-centred care is increasingly promoted, empowering patients to become more involved in their treatment rather than being passive recipients of care (Barnes et al. 2013). Haemodialysis is typically required three times a week, with fluid management decision-making occurring at each treatment session (Ahmed et al. 2017). However, no research has yet explored how haemodialysis patients' perceptions of their fluid management may impact upon this decision-making. OBJECTIVES: This study sought to explore patients' perceptions of their fluid management. METHOD: DESIGN, PARTICIPANTS & APPROACH: Semi-structured interviews were conducted with 12 patients undergoing in-hospital haemodialysis treatment. These were digitally recorded one-to-one interviews to allow for verbatim transcription. The data was analysed by thematic analysis, generating thematic patterns across patients' experiences, control and knowledge of their fluid management. RESULTS: Five themes were produced: determining who has the expertise, impediments affecting patients' lifestyle, additional difficulty of experiencing comorbidities, perceived quality of care, and establishing consistency. CONCLUSIONS: Despite varied levels of patient participation in their treatment, overall there appears to be a limited understanding of specific areas of fluid management. The implications for further research and the development of shared-care are discussed.

Acceptability of Mobile Health Technology for Promoting Fluid Consumption in Patients With Nephrolithiasis.

OBJECTIVE: To evaluate kidney stone patients' interest in lifestyle behavior modification and a variety of mobile health (mHealth) technologies to improve adherence to fluid consumption recommendations for the prevention of nephrolithiasis. Of particular interest was the acceptability of various intervention components for the design of a stone-specific mHealth technology. MATERIALS AND METHODS: Using a cross-sectional design, adult patients with a diagnosis of kidney stones (n = 94) were recruited from outpatient clinics to complete a three-part questionnaire. RESULTS: Patients reported being willing to make lifestyle changes to prevent kidney stones (97%). The majority of the patients recalled the recommendation to increase fluid intake (93%) but few monitored their daily fluid intake (30%). Most patients had never installed an app (95%) or owned a device (100%) to help with increasing fluid consumption, but believed an app or device could improve their adherence (72%) and would be interested in using an app or device (86%). The mHealth intervention components most widely perceived as useful included automated lapse detection with notifications, educational materials, self-monitoring tools, scheduler with prompts and/or reminders and/or notifications, connected water bottles and text message reminders to drink. CONCLUSION: Patients are interested in lifestyle behavior change to prevent stones but technology has not been widely adopted to improve adherence to fluid intake recommendations for stone prevention. This study identified a number of viable mHealth intervention components that should be considered when designing a stone-specific mHealth technology to support adherence to increased fluid consumption recommendations.

Use of Artificial Hydration at the End of Life: A Survey of Australian and New Zealand Palliative Medicine Doctors.

BACKGROUND: Dying is ubiquitous, yet the optimal management of hydration in the terminal phase is undetermined. Palliative care (PC) doctors' practices may act as a de facto measure of the benefits and burdens of artificial hydration (AH) use. OBJECTIVE: To identify PC doctors' AH prescribing practices for imminently dying patients and possible influencing factors. METHODS: An online survey of doctors belonging to the Australian and New Zealand Society of Palliative Medicine. RESULTS: One hundred and thirty-six surveys were completed (30% response rate). AH use for patients in the prognosticated last week of life was low: 77% of respondents prescribed AH to 0-10% of patients and 3% of respondents prescribed to more than 20%. The most common reason for prescribing AH was palliation of family/patient concern rather than a physical symptom. The majority thought there was no effect of AH on survival, or on symptoms of fatigue (90%), reduced level of consciousness (88%), agitation (75%), nausea (69%), vomiting (68%), myoclonus (66%), thirst (65%), delirium (62%), cough (57%), or bowel obstruction (50%). AH was thought to worsen subcutaneous edema (94%), upper respiratory tract secretions (85%), ascites (73%), physical discomfort (72%), dyspnea (62%), and urinary symptoms (57%). CONCLUSION: PC doctors from Australia and New Zealand reported lower use of AH for dying patients compared to international counterparts. The study showed high concordance in respondents' opinions: most thought AH was unlikely to provide clinical benefit and might cause harm. Further studies are needed to determine best practice of AH use at the end of life.

Disentangling the effects of a multiple behaviour change intervention for diarrhoea control in Zambia: a theory-based process evaluation.

BACKGROUND: Diarrhoea is a leading cause of child death in Zambia. As elsewhere, the disease burden could be greatly reduced through caregiver uptake of existing prevention and treatment strategies. We recently reported the results of the Komboni Housewives intervention which tested a novel strategy employing motives including affiliation and disgust to improve caregiver practice of four diarrhoea control behaviours: exclusive breastfeeding; handwashing with soap; and correct preparation and use of oral rehydration salts (ORS) and zinc. The intervention was delivered via community events (women's forums and road shows), at health clinics (group session) and via radio. A cluster randomised trial revealed that the intervention resulted in a small improvement in exclusive breastfeeding practices, but was only associated with small changes in the other behaviours in areas with greater intervention exposure. This paper reports the findings of the process evaluation that was conducted alongside the trial to investigate how factors associated with intervention delivery and receipt influenced caregiver uptake of the target behaviours. METHODS: Process data were collected from the eight peri-urban and rural intervention areas throughout the six-month implementation period and in all 16 clusters 4-6 weeks afterwards. Intervention implementation (fidelity, reach, dose delivered and recruitment strategies) and receipt (participant engagement and responses, and mediators) were explored through review of intervention activity logs, unannounced observation of intervention events, semi-structured interviews, focus groups with implementers and intervention recipients, and household surveys. Evaluation methods and analyses were guided by the intervention's theory of change and the evaluation framework of Linnan and Steckler. RESULTS: Intervention reach was lower than intended: 39% of the surveyed population reported attending one or more face-to-face intervention event, of whom only 11% attended two or more intervention events. The intervention was not equally feasible to deliver in all settings: fewer events took place in remote rural areas, and the intervention did not adequately penetrate communities in several peri-urban sites where the population density was high, the population was slightly higher socio-economic status, recruitment was challenging, and numerous alternative sources of entertainment existed. Adaptations made by the implementers affected the fidelity of implementation of messages for all target behaviours. Incorrect messages were consequently recalled by intervention recipients. Participants were most receptive to the novel disgust and skills-based interactive demonstrations targeting exclusive breastfeeding and ORS preparation respectively. However, initial disgust elicitation was not followed by a change in associated psychological mediators, and social norms were not measurably changed. CONCLUSIONS: The lack of measured behaviour change was likely due to issues with both the intervention's content and its delivery. Achieving high reach and intensity in community interventions delivered in diverse settings is challenging. Achieving high fidelity is also challenging when multiple behaviours are targeted for change. Further work using improved tools is needed to explore the use of subconscious motives in behaviour change interventions. To better uncover how and why interventions achieve their measured effects, process evaluations of complex interventions should develop and employ frameworks for investigation and interpretation that are structured around the intervention's theory of change and the local context. TRIAL REGISTRATION: The study was registered as part of the larger trial on 5 March 2014 with ClinicalTrials.gov: NCT02081521 .

Artificial Hydration at the End of Life.

Initiation or continuation of artificial hydration (AH) at the end of life requires unique considerations. A combination of ethical precedents and medical literature may provide clinical guidance on how to use AH at the end of life. The purpose of this review is to describe the ethical framework for and review current literature relating to the indications, benefits, and risks of AH at the end of life. Provider, patient, and family perspectives will also be discussed.

Dietary and fluid restriction perceptions of patients undergoing haemodialysis: an exploratory study.

AIMS AND OBJECTIVES: To explore the perspectives of patients undergoing haemodialysis in Singapore on an imposed dietary and fluid restriction regime. BACKGROUND: Adherence to prescribed dietary and fluid restriction constructs the fundamental basis of self-care with improved morbidity and mortality. However, most patients have struggled to adhere in this aspect. Existing studies have presented limited understanding on the facilitators and barriers of dietary and fluid adherence among haemodialysis patients. DESIGN: An exploratory qualitative study. METHODS: A purposive sample of 14 patients undergoing haemodialysis was recruited from a renal unit of a tertiary hospital in Singapore. Data were collected through face-to-face individual interviews and subsequently analysed by thematic analysis. RESULTS: Four themes emerged: (1) Pessimism, (2) Existing struggles, (3) Perceived quality of support, and (4) Immensity of self-discipline. CONCLUSIONS: The imposed dietary and fluid restriction is a constant struggle and a cause of suffering among haemodialysis patients in Singapore. Nonetheless, they are generally submissive to their fluid restrictions for the sake of survival or to meet the expectations of their loved ones. The imposed dietary restrictions are generally neglected. RELEVANCE TO CLINICAL PRACTICE: The findings from this study can provide useful information in reviewing existing educational strategies, policies and nursing care. This is especially important because most patients exhibit high reliance on healthcare professionals.

Opinions about the new law on end-of-life issues in a sample of french patients receiving palliative care.

BACKGROUND: In February 2nd 2016, the French government enacted the Claeys-Leonetti law that forbade euthanasia and established the right to deep and continuous sedation for end-of-life patients. Moreover, the law also obliges clinicians to abide by any advance directives regarding treatment and investigation, except in cases where they are "obviously inappropriate" in a given medical situation, or in cases of emergency, in order to allow medical staff to take time to assess the patient's situation. Artificial feeding and hydration are considered as treatment. The aim of this report is to investigate individuals receiving palliative care about their opinion about euthanasia, about advance directives, about the right to deep and continuous sedation, and the right to stopping artificial feeding and hydration. METHODS: The study was an opinion survey conducted among patients treated in two different palliative care institutions: a palliative care unit at the University Hospital (Timone, Marseille, France) and a non-profit association palliative care home ("La Maison", Gardanne, France). Face-to-face interviews were performed by two investigators. The survey included sociodemographics, clinical data, and opinions about euthanasia, deep and continuous sedation, stopping artificial feeding and hydration, and advance directives. RESULTS: Forty patients were interviewed. The mean age was 59.8 years (standard deviation 12). Fifty three percent reported opposition to legalized euthanasia. Eighty three percent were in favour of the right to deep and continuous sedation in patients with refractory pain, 75% when it concerns a patient unable to express their wishes, and 68% when the patient decides to stop vital treatment. Fifty eight percent reported that artificial nutrition and hydration should be considered as care. Fifty eight percent of the patients interviewed would like to see doctors follow the express wishes contained in advance care directives and 53% that advance directives should be subject to a validity period. CONCLUSIONS: This work demonstrates the feasibility of discussing sensitive issues such as euthanasia, continuous and deep sedation and cessation of care with patients receiving palliative care. These preliminary results point to the need to perform a larger study in order to find determinant factors in this specific situation and to incorporate them into thinking about end-of-life laws.

Withholding versus withdrawing treatment: artificial nutrition and hydration as a model.

PURPOSE OF REVIEW: This article explores various cultural perspectives of withholding and withdrawing of life-sustaining treatment utilizing a case involving artificial nutrition and hydration (ANH) to guide ethical discussion. RECENT FINDINGS: In the United States, there is a general consensus in the medical, ethical, and legal communities that the withholding and withdrawing of life-sustaining treatment are morally equivalent at the end of life. Despite this consensus, the withdrawal of treatment is still emotionally difficult, particularly with ANH. Recent literature challenges the evidence base that feeding tubes for people with advanced dementia lead to significant harm. In light of these new findings, we will reconsider end-of-life decision making that concerns ANH to determine whether these new findings undermine previous ethical arguments and to consider how to best educate and support patients and families during the decision-making process. SUMMARY: Despite many believing that there is no ethical, medical, or moral difference between withholding and withdrawing of life-sustaining treatment, there is no denying it is emotionally taxing, particularly withdrawal of ANH. Upholding the patient's values during high-quality shared decision making, facilitating rapport, and utilizing time limited trials will help, even when treatment is considered medically ineffective.

Prevalence, risk factors and treatment practices in diarrhoeal diseases in south India.

OBJECTIVES: This study was done to determine the risk factors, management practices and awareness about diarrhoea. METHODS: It was a cross sectional study done in a semi urban and rural areas of South Canara district of India in February 2013. A total of 167 households (575 study population) chosen systematic randomly were visited and one adult member in each house was interviewed. The houses were also inspected to assess the living conditions. RESULTS: Mean age of study population was 31.1 ± 20.2 years. The period prevalence of diarrhoea was 69 (12 %). Commonest associated symptoms in cases of diarrhoea were fever 30 (43.4 %) followed by abdominal cramps 29 (42 %). Nearly half of the cases with diarrhoea 34 (49.3 %) did not take any medications. Commonest treatment taken was allopathic medicines 26 (37.8 %) followed by home remedies 8 (22.9 %). Age ≤10 years (p < 0.001) was associated with risk of developing diarrhoea using binary logistic regression analysis. Among the 167 participants, awareness level about the disease was poor among 16 (9.6 %) and moderate among 149 (89.2 % participants). Awareness level was more among females (p = 0.001) and literate participants (p = 0.013). One hundred and sixteen (69.5 %) participants were not aware of any sign or symptom of dehydration other than loose stools. Majority of the participants 138 (82.6 %) preferred home remedies as the initial management of diarrhoea. Misconception about fluid restriction in diarrhoea was stated by 12(7.2 %) participants. CONCLUSION: Public education program on proper feeding and management practices is required to address the various issues identified and for containment of diarrhoea cases in future.

Perceptions of health professionals on subcutaneous hydration in palliative care: A qualitative study.

BACKGROUND: Evidence indicates that hypodermoclysis is as safe and effective as intravenous rehydration in the treatment of the symptomatology produced by mild to moderate dehydration in patients for whom oral route administration is not possible. However, the knowledge about the use of the subcutaneous hydration and its correlates is still limited. AIM: To explore the perceptions, attitudes and opinions of health professionals in palliative care on the administration of subcutaneous hydration. DESIGN: This is a qualitative focus group study with health professionals of palliative care. Four focus groups were carried out until data saturation. A qualitative content analysis was performed. SETTING/PARTICIPANTS: A total of 37 participants, physicians and nurses, were recruited from different services of palliative care in Spain. RESULTS: In all, 856 meaning units were identified, from which 56 categories were extracted and grouped into 22 sub-themes, which were distributed among four themes: 'factors which influence the hydration decision', 'factors related to the choice of the subcutaneous route for hydration', 'the subcutaneous hydration procedure' and 'performance guidelines and/or protocols'. CONCLUSIONS: Variables which most often influence the use of subcutaneous route to hydration are those that are linked to the characteristics of the patient, the team and the family, and other like the context and professionals' subjective perceptions about this medical practice.

Evidence of improved fluid management in patients receiving haemodialysis following a self-affirmation theory-based intervention: A randomised controlled trial.

OBJECTIVE: Haemodialysis patients are at risk of serious health complications; yet, treatment non-adherence remains high. Warnings about health risks associated with non-adherence may trigger defensive reactions. We studied whether an intervention based on self-affirmation theory reduced resistance to health-risk information and improved fluid treatment adherence. DESIGN: In a cluster randomised controlled trial, 91 patients either self-affirmed or completed a matched control task before reading about the health-risks associated with inadequate fluid control. OUTCOME MEASURES: Patients' perceptions of the health-risk information, intention and self-efficacy to control fluid were assessed immediately after presentation of health-risk information. Interdialytic weight gain (IDWG), excess fluid removed during haemodialysis, is a clinical measure of fluid treatment adherence. IDWG data were collected up to 12 months post-intervention. RESULTS: Self-affirmed patients had significantly reduced IDWG levels over 12 months. However, contrary to predictions derived from self-affirmation theory, self-affirmed participants and controls did not differ in their evaluation of the health-risk information, intention to control fluid or self-efficacy. CONCLUSION: A low-cost, high-reach health intervention based on self-affirmation theory was shown to reduce IDWG over a 12-month period, but the mechanism by which this apparent behaviour change occurred is uncertain. Further work is still required to identify mediators of the observed effects.